Developmental programming of the HPA axis and related behaviours: epigenetic mechanisms

It has been approximately 30 years since the seminal discoveries of David Barker and his colleagues, and research is beginning to unravel the mechanisms that underlie developmental programming. The early environment of the embryo, foetus and newborn have been clearly linked to altered hypothalamic–pituitary–adrenal (HPA) function and related behaviours through the juvenile period and into adulthood. A number of recent studies have shown that these effects can pass across multiple generations. The HPA axis is highly responsive to the environment, impacts both central and peripheral systems and is critical to health in a wide variety of contexts. Mechanistic studies in animals are linking early exposures to adversity with changes in gene regulatory mechanisms, including modifications of DNA methylation and altered levels of miRNA. Similar associations are emerging from recent human studies. These findings suggest that epigenetic mechanisms represent a fundamental link between adverse early environments and developmental programming of later disease. The underlying biological mechanisms that connect the perinatal environment with modified long-term health outcomes represent an intensive area of research. Indeed, opportunities for early interventions must identify the relevant environmental factors and their molecular targets. This new knowledge will likely assist in the identification of individuals who are at risk of developing poor outcomes and for whom early intervention is most effective.

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Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress

Cellular and Molecular Life Sciences ◽

10.1007/s00018-020-03566-z ◽

2020 ◽

Vol 77 (23) ◽

pp. 4861-4898

Author(s):

Efthimia R. Christoforou ◽

Amanda N. Sferruzzi-Perri

Keyword(s):

Molecular Mechanisms ◽

Metabolic Diseases ◽

Developmental Programming ◽

In Utero ◽

Postnatal Life ◽

Molecular Pathways ◽

Epigenetic Mechanisms ◽

Metabolic Dysfunction ◽

Rodent Models ◽

Human Lifespan

Abstract The results of different human epidemiological datasets provided the impetus to introduce the now commonly accepted theory coined as ‘developmental programming’, whereby the presence of a stressor during gestation predisposes the growing fetus to develop diseases, such as metabolic dysfunction in later postnatal life. However, in a clinical setting, human lifespan and inaccessibility to tissue for analysis are major limitations to study the molecular mechanisms governing developmental programming. Subsequently, studies using animal models have proved indispensable to the identification of key molecular pathways and epigenetic mechanisms that are dysregulated in metabolic organs of the fetus and adult programmed due to an adverse gestational environment. Rodents such as mice and rats are the most used experimental animals in the study of developmental programming. This review summarises the molecular pathways and epigenetic mechanisms influencing alterations in metabolic tissues of rodent offspring exposed to in utero stress and subsequently programmed for metabolic dysfunction. By comparing molecular mechanisms in a variety of rodent models of in utero stress, we hope to summarise common themes and pathways governing later metabolic dysfunction in the offspring whilst identifying reasons for incongruencies between models so to inform future work. With the continued use and refinement of such models of developmental programming, the scientific community may gain the knowledge required for the targeted treatment of metabolic diseases that have intrauterine origins.

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Beyond the monoaminergic hypothesis: neuroplasticity and epigenetic changes in a transgenic mouse model of depression

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2012.0212 ◽

2012 ◽

Vol 367 (1601) ◽

pp. 2485-2494 ◽

Cited By ~ 79

Author(s):

Renaud Massart ◽

Raymond Mongeau ◽

Laurence Lanfumey

Keyword(s):

Mouse Model ◽

Transgenic Mouse ◽

Hpa Axis ◽

Glucocorticoid Receptors ◽

Clock Genes ◽

Transgenic Mouse Model ◽

Epigenetic Mechanisms ◽

Epigenetic Changes ◽

Pharmacological Treatments ◽

Antidepressant Agents

The monoamine hypothesis of depression has dominated our understanding of both the pathophysiology of depression and the action of pharmacological treatments for the last decades, and it has led to the production of several generations of antidepressant agents. However, there are serious limitations to the current monoamine theory, and additional mechanisms, including hypothalamic–pituitary–adrenal (HPA) axis dysfunctions, as well as neurodegenerative and inflammatory alterations, are potentially associated with the pathogenesis of mood disorders. Moreover, new data have recently indicated that epigenetic mechanisms such as histone modifications and DNA methylation could affect diverse pathways leading to depression-like behaviours in animal models. In a transgenic mouse model of depression, in which a downregulation of glucocorticoid receptors (GR) causes a deficit in the HPA axis feedback control , besides alterations in monoamine neurotransmission and neuroplasticity, we found modifications in the expression of many proteins involved in epigenetic regulation, as well as clock genes, in the hippocampus and the frontal cortex, that might be central in the genesis of depressive-like behaviours.

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Developmental programming of O2 sensing by neonatal intermittent hypoxia via epigenetic mechanisms

Respiratory Physiology & Neurobiology ◽

10.1016/j.resp.2012.07.016 ◽

2013 ◽

Vol 185 (1) ◽

pp. 105-109 ◽

Cited By ~ 14

Author(s):

Jayasri Nanduri ◽

Nanduri R. Prabhakar

Keyword(s):

Intermittent Hypoxia ◽

Developmental Programming ◽

Epigenetic Mechanisms ◽

O2 Sensing

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Epigenetic mechanisms in developmental programming of adult disease

Drug Discovery Today ◽

10.1016/j.drudis.2011.09.008 ◽

2011 ◽

Vol 16 (23-24) ◽

pp. 1007-1018 ◽

Cited By ~ 61

Author(s):

Man Chen ◽

Lubo Zhang

Keyword(s):

Developmental Programming ◽

Epigenetic Mechanisms ◽

Adult Disease

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Epigenetic Programming of Adipose Tissue in the Progeny of Obese Dams

Current Genomics ◽

10.2174/1389202920666191118092852 ◽

2019 ◽

Vol 20 (6) ◽

pp. 428-437 ◽

Cited By ~ 1

Author(s):

Simon Lecoutre ◽

Kelvin H.M. Kwok ◽

Paul Petrus ◽

Mélanie Lambert ◽

Christophe Breton

Keyword(s):

Adipose Tissue ◽

Maternal Obesity ◽

Metabolic Diseases ◽

Tissue Expansion ◽

Developmental Programming ◽

Epigenetic Mechanisms ◽

Epigenetic Programming ◽

Important Player ◽

Health And Disease ◽

Adipose Tissue Remodeling

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and the resulting accelerated growth in neonates predispose offspring to obesity and associated metabolic diseases that may persist across generations. In this context, the adipose tissue has emerged as an important player due to its involvement in metabolic health, and its high potential for plasticity and adaptation to environmental cues. Recent years have seen a growing interest in how maternal obesity induces long-lasting adipose tissue remodeling in offspring and how these modifications could be transmitted to subsequent generations in an inter- or transgenerational manner. In particular, epigenetic mechanisms are thought to be key players in the developmental programming of adipose tissue, which may partially mediate parts of the transgenerational inheritance of obesity. This review presents data supporting the role of maternal obesity in the developmental programming of adipose tissue through epigenetic mechanisms. Inter- and transgenerational effects on adipose tissue expansion are also discussed in this review.

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Looking beyond the DNA sequence: the relevance of DNA methylation processes for the stress–diathesis model of depression

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2012.0251 ◽

2013 ◽

Vol 368 (1615) ◽

pp. 20120251 ◽

Cited By ~ 67

Author(s):

Linda Booij ◽

Dongsha Wang ◽

Mélissa L. Lévesque ◽

Richard E. Tremblay ◽

Moshe Szyf

Keyword(s):

Dna Methylation ◽

Hpa Axis ◽

Life Experience ◽

Gene Expression Programming ◽

Perinatal Period ◽

Future Research ◽

Epigenetic Mark ◽

Epigenetic Mechanisms ◽

Depression Vulnerability ◽

Early Life Experience

The functioning of the hypothalamic–pituitary–adrenal (HPA) axis and serotonergic (5-HT) system are known to be intertwined with mood. Alterations in these systems are often associated with depression. However, neither are sufficient to cause depression in and of themselves. It is now becoming increasingly clear that the environment plays a crucial role, particularly, the perinatal environment. In this review, we posit that early environmental stress triggers a series of epigenetic mechanisms that adapt the genome and programme the HPA axis and 5-HT system for survival in a harsh environment. We focus on DNA methylation as it is the most stable epigenetic mark. Given that DNA methylation patterns are in large part set within the perinatal period, long-term gene expression programming by DNA methylation is especially vulnerable to environmental insults during this period. We discuss specific examples of genes in the 5-HT system (serotonin transporter) and HPA axis (glucocorticoid receptor and arginine vasopressin enhancer) whose DNA methylation state is associated with early life experience and may potentially lead to depression vulnerability. We conclude with a discussion on the relevance of studying epigenetic mechanisms in peripheral tissue as a proxy for those occurring in the human brain and suggest avenues for future research.

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